Many human neurodegenerative diseases are poorly understood and untreatable, including Parkinson's (PD), Alzheimer's and Huntington's diseases. For some familial forms, mutations in specific genes are known, allowing pathology to be modeled in simpler systems in order to define mechanisms and pioneer novel treatments. Toward this end, we applied the power of fly genetics to the problem of neurodegeneration by developing models for human disease in Drosophila. Here, we propose to further characterize mechanisms of alpha-synuclein (alpha-syn) associated loss of dopaminergic (DA) neuron integrity, and to study a newly-identified PD-like disorder gene, DJ-1, and its role in protection from oxidative stress. Mutations in alpha-syn are pathogenic for hereditary PD, and wild-type alpha-syn is the major protein component of the pathological aggregates called Lewy bodies that characterize sporadic PD and other synucleinopathies. In Drosophila, expression of alpha-syn compromises the integrity of DA neurons. To further investigate this, in Aim 1 we propose to generate modified forms of alpha-syn and then characterize in detail their toxicity in vivo. Modifications of interest include new hereditary mutations, truncation, and phosphorylation, which are associated with PD or have striking effects on alpha-syn fibrillization in vitro.
In Aim 2, given strong links between environmental toxins and development of PD, we will expand our studies of Drosophila models to the detailed characterization of a new PD-like disorder gene, DJ-1. Preliminary studies reveal that null mutation of fly DJ-1 homologues strikingly enhances sensitivity to select oxidative toxins associated with PD, including paraquat and rotenone. Since oxidative damage is thought to be critically involved in both genetic and sporadic forms of PD, study of DJ-1 homologues will reveal new insight into these links.
In Aim 3, we will apply the power of Drosophila genetics to address conserved features of alpha-syn and DJ-1-associated pathology, in order to pioneer new approaches to understand and treat human neurodegeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG009215-17
Application #
7309728
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
17
Fiscal Year
2006
Total Cost
$263,532
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Tosto, Giuseppe; Monsell, Sarah E; Hawes, Stephen E et al. (2015) Pattern of extrapyramidal signs in Alzheimer's disease. J Neurol 262:2548-56
Paumier, Katrina L; Luk, Kelvin C; Manfredsson, Fredric P et al. (2015) Intrastriatal injection of pre-formed mouse ?-synuclein fibrils into rats triggers ?-synuclein pathology and bilateral nigrostriatal degeneration. Neurobiol Dis 82:185-199
Kalia, Lorraine V; Lang, Anthony E; Hazrati, Lili-Naz et al. (2015) Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA Neurol 72:100-5
Mata, Ignacio F; Leverenz, James B; Weintraub, Daniel et al. (2014) APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease. JAMA Neurol 71:1405-12
Motsinger-Reif, Alison A; Zhu, Hongjie; Kling, Mitchel A et al. (2013) Comparing metabolomic and pathologic biomarkers alone and in combination for discriminating Alzheimer's disease from normal cognitive aging. Acta Neuropathol Commun 1:28
Arnold, Steven E; Toledo, Jon B; Appleby, Dina H et al. (2013) Comparative survey of the topographical distribution of signature molecular lesions in major neurodegenerative diseases. J Comp Neurol 521:4339-55
Kaddurah-Daouk, R; Zhu, H; Sharma, S et al. (2013) Alterations in metabolic pathways and networks in Alzheimer's disease. Transl Psychiatry 3:e244
Couthouis, Julien; Hart, Michael P; Erion, Renske et al. (2012) Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Hum Mol Genet 21:2899-911
Hu, William T; Holtzman, David M; Fagan, Anne M et al. (2012) Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease. Neurology 79:897-905
Chen-Plotkin, Alice S; Unger, Travis L; Gallagher, Michael D et al. (2012) TMEM106B, the risk gene for frontotemporal dementia, is regulated by the microRNA-132/212 cluster and affects progranulin pathways. J Neurosci 32:11213-27

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